Yersinia pestis, the causative agent of the plague, has been weaponized as an agent of biowarfare. The deliberate release of weaponized Y. pestis would likely occur via aerosol dissemination resulting in an outbreak of the highly lethal and contagious pneumonic plague. Therefore there is a critical need for new agents to combat infection by the antibiotic-resistant, weaponized bacteria. Y. pestis, like all intracellular pathogens, subverts signaling events within the host cell in order to establish and maintain infection. Because the host cell's signaling events are as essential to establishing and maintaining infection as is the pathogen's own signaling machinery, they present attractive targets for anti-infective agents. We demonstrate that targeting the host cell is effective at 1) reducing the viability of the internalized pathogen and 2) protecting the host cell from pathogen-induced cytoskeletal remodeling. Luna Innovations Incorporated, Dr. James B. Bliska (SUNY Stony Brook), Dr. Sidney M. Hecht (University of Virginia), Dr. Louis E. Holland, III (Illinois Institute of Technology Research Institute), Dr. Deborah A. Lannigan (University of Virginia) and Dr. George A. O'Doherty (West Virginia University) are extending these exciting findings to develop an anti-Yersinia pestis therapeutic for clinical application. The program will focus on optimization of our drug to improve its therapeutic activity as an anti-Y. pestis agent;synthesizing sufficient quantities of the optimized analogs for efficacy studies in in vivo models of infection;and performing genetic toxicological analysis as well as pharmacokinetic studies to establish the drug metabolism and duration of action profiles. The intention of these studies is to perform essential benchmarks with our novel biodefense agent in preparation for submission of an investigational new drug (IND) application with the FDA. PUBLIC HEALTH RELEVANCE: Many bacteria subvert the host cell's signaling machinery in order to establish and maintain infection. Using a drug that we discovered and characterized, we have demonstrated that modulating the host cell's machinery essential to the bacteria is an effective way of interfering with the ability of bacteria to survive inside the host cell. The proposed research is designed to develop our novel anti-infective agent toward clinical application as an anti-Yersinia pestis agent.